Parkinson's disease (PD) is a relatively common neurodegenerative disease associated with progressive loss of dopaminergic neurons of the substantia nigra (SN) and locus coeruleus. The major clinical symptoms of PD are body rigidity, hypokinesia, and postural instability linked with trembling extremities. The cause of non-familial PD remains unclear. There are several theories regarding the possible factors behind the neuronal degeneration. These include environmental toxins, genetic factors, proteasomal and mitochondrial dysfunction, as well as free radical mediated cell death/oxidative stress. PD clinical features also comprise non-motor manifestations among which, dementia is the most important. In approximately 40% of patients, PD is complicated by cognitive impairment. Moreover, in addition to age, dementia is an independent predictor of mortality, whereas age at onset of PD and severity of neurological symptoms are not.
COMT inhibitors reduce the peripheral enzyme with greater potency than the enzyme present in the central nervous system, tolcapone does penetrate the blood-brain barrier and inhibits the COMT activity of the brain. A recent “proof-of-concept” study shows that this drug enhances memory and executive cognition and the physiologic efficiency of prefrontal cortical information processing in normal volunteers.
One of the earliest biochemical changes seen in PD patients is a decrease in reduced glutathione (GSH) levels; GSH is a major component of cellular antioxidant defenses. A decrease in GSH levels also occurs in incidental Lewy body disease, which is thought to be an asymptomatic precursor to PD. This suggests that GSH depletion in the SN may play a more active role in PD pathogenesis than previously thought. Indeed recent studies reveal that GSH depletion may be actively involved in complex I inhibition, disruption of the ubiquitin-proteasome system, and may have effects that affect the inflammatory processes seen in PD.
Managing acute pathology of often relies on the addressing underlying pathology and symptoms of the disease. There is currently a need in the art for new compositions to treatment of Parkinson's disease.